The proposed study is based on the hypothesis that substance P (SP) is released from sensory nerve terminals in the heart and exerts local effects which are important in the normal regulation of cardiac function and/or in cardiac pathophysiology. Conceptual support for this hypothesis comes from studies of SP involvement in regulation of the airways where there is strong evidence for release of SP from local sensory nerve terminals in response to airways irritants and subsequent SP-mediated airway constriction and edema. SP-containing nerve fibers are found at several sites in the heart, and SP-like immunoreactivity can be released from these fibers. Exogenous SP has been shown to affect various aspects of cardiac function, including coronary blood flow, but there are some inconsistencies in the literature which need to be resolved. More direct study of the function of endogenous SP is also needed. The proposed study will address the latter two points. In the first series of proposed experiments, the pharmacological actions of SP on the isolated, perfused guinea-pig heart will be examined. Effects of SP on perfusion pressure, ventricular tension and ventricular rate will be measured. Since hearts will be perfused at a constant rate, perfusion pressure will be directly proportional to coronary vascular resistance. Special attention will be given to the possible role of vascular endothelium in the response of the coronary vasculature to SP and the involvement of histamine and autonomic mediators in the cardiac actions of SP. In the second phase of the study, experiments will be done to determine if SP is a mediator which contributes to the coronary vasodilation produced by hypoxia and coronary occlusion. Initially, the effect of hypoxia and coronary occlusion on release of SP will be determined. Next, the response of the coronary vasculature to hypoxia and coronary occlusion will be examined in hearts which have had SP depleted by capsaicin pretreatment. The proposed experiments would contribute to the long-term goal of determining the importance of neuropeptides in cardiac physiology and pathophysiology.